Homeobox-containing (Hox) genes encode transcriptional factors that regulate cellular positioning and differentiation in the mammalian embryo. Targeted disruptions of specific mouse Abdominal B (AbdB)-related Hox genes have resulted in abnormal female reproductive tract development as well as sterility. The targeted disruption of AbdB-related Hox genes, however, assumes a role for these AbdB-related Hox genes in the function of the adult reproductive system. Specifically, the abnormal development and differentiation of the reproductive system produced by targeted disruptions of AbdB-related Hox genes may interfere with correct interpretation of adult reproductive tract physiology. Furthermore, the genetic regulation between the various AbdB-related Hox genes in the developing mouse female reproductive system has not been previously examined. The applicant's objective is to demonstrate that mouse AbdB-related Hox genes are critical in regulating female reproductive system development and function. To accomplish this objective, three specific aims are presented: 1) Inducible gene targeted disruption of Hoxa10 and Hoxa11 genes in the murine model will be developed; 2) Adult reproductive function will be examined in the induced Hoxa10 and Hoxa11 female mutants and characterized at the gross and cellular level; 3) Candidate molecular components will be studied in the same induced female mutants compared to normal females; and 4) Hox gene regulation of female reproductive tract development will be determined through combinations of targeted Hox disruptions. The overall long-term goal is to elucidate the genetic regulation critical in murine female reproductive tract development and function. Inducible knockouts are an innovative approach in investigating gene disruption in an adult animal. Dr. Capecchi's development of gene targeting and his laboratory's continuing Hox genetic investigations provide a fertile environment to complete this proposal. This puts the applicant in a unique position in having the capacity to conduct the entire spectrum of basic studies that will be required for this proposal. The applicant expects that his results will help guide future studies in human reproductive system function and will ultimately impact on the field of reproductive biology. Under the direction of Dr. Mario Capecchi at the University of Utah, Dr. Kenneth Wong is in a unique position to learn and conduct contemporary gene targeting and genetic investigations. The NICHD Mentored Scientist Clinical Development Award will provide the candidate with the opportunity to develop into a future independent investigator.